Patent GB-998835-A (GB)
Title: (ª-alkylideneacyl)-phenyl compounds
IPC: C07C51/08
Filed: 1962-01-16
Abstract: The invention comprises compounds of the general formula <PICT:0998835/C2/1> wherein each of R, R1 and R2 is a hydrogen or halogen atom or a halomethyl, hydroxy, C1- 5 aliphatic, C1- 5 aliphatic oxy, C1- 5 aliphatic-thio, alicyclic, mononuclear aryl, mononuclear aryl substituted - C1- 5 - aliphatic, mononuclear arylsubstituted C1- 5 aliphatic thio, mononuclear aryloxy, or mononuclear aryl-thio radical with the proviso that not all of R, R1 and R2 are hydrogen atoms, or R and R2 are joined to form with the carbon atoms to which they are attached a 5- or 6-membered carbocyclic ring; each of R3, R4, R5 and R6 is a hydrogen atom or a halomethyl, C1- 5-aliphatic, mononuclear aryl, C1- 5 aliphatic-oxy, hydroxy, acylamino or nitroradical or R3 and R4 are joined to form with the ring carbons to which they are attached a 5- or 6-membered carbocyclic ring; A is an oxygen or sulphur atom; B is a divalent C1- 5 aliphatic, divalent C1- 5 alkylene oxy or divalent C1- 5-aliphatic-mono-nuclear aryl radical; and X is a hydroxyl or a salt of a hydroxyl radical or is an alkoxy, amino or hydrazino radical, (in the above definitions the aliphatic, aliphatic-oxy and aliphatic-thio groups may be straight-chain or branched-chain, saturated or unsaturated, and may have amino, halomethyl, carboxyl, substituted carboxyl, hydroxyl, alkylthio, arylthio or nitro substituents; the alicyclic groups may also be substituted as for the aliphatic groups; the aryl, aryloxy, arylthio, and arylaliphatic groups may be substituted by C1-5-alkyl, C1-5 alkoxy, C1-5 alkylthio, hydroxy, or halomethyl groups or halogen atoms; and amides include substituted amides containing the group NR7R8, where R7 and R8 are aliphatic or aromatic groups either substituted or unsubstituted or R7 and R8 are joined to form a heterocyclic ring) and the preparation thereof (a) by reacting an appropriate aliphatic acylphenyl compound with a salt of a secondary amine in the presence of paraformaldehyde and treating the Mannich base so formed with a weak base; (b) by brominating an appropriate a ,b -dialiphatic acetylphenyl derivative and treating the resulting product with a dehydrohalogenating agent, (c) by condensing an appropriate aliphatic acyl phenyl compound in alkaline medium with an arylaldehyde and if desired, (d) by converting the product of any of the above processes into an acid, ester, amide or hydrazide thereof.  Saturated acylphenoxy- and acylphenylthioderivatives of monocarboxylic acids used as starting materials are prepared by Friedel-Craft reaction or by hydrogenation of the a -alkylideneacyl)phenyl derivatives of the invention; acylphenoxyacetic acid and other acylphenoxy derivatives of monocarboxylic acids from the acylphenol and a haloacetate or other ester; acylphenols from the phenol and a carboxylic acid in the presence of boron trifluoride; orthoacylphenols by the Fries arrangement by esterifying a phenol with an acid halide and heating the ester with aluminium chloride; 4-chloro-3-propionylphenol by nitration of 2-chloropropiophenone to 2 - chloro - 5 - nitropropiophenone, reduction of this to 2-chloro-5-aminopropiophenone and diazotization; 2,4-dimethyl-5-butyrylphenol by diazotization of the amine; methyl 3-(bromomethyl)-benzoate and 2-(bromomethyl)-benzoate by bromination of the methylbenzoyl chloride in methanol; 21,61-dichloro-31 -hydroxybutyrophenone by Grignard reaction between 2,6-dichloro-3-methoxy benzaldehyde and propyl magnesium bromide to give 2,6-dichloro - 3 - methoxy - a  - propylbenzyl alcohol, oxidation to 21,61 - dichloro - 31 - methoxy - butyrophenone and hydrolysis; ethyl 4-chloromethylbenzoate by chlorination of p-tolunitrile to 4-chloromethylbenzonitrile, hydrolysis to 4-chloromethylbenzoic acid and esterification; and 3 - methyl - 4 - phenoxyacetylphenoxyacetic acid from phenol and the 4-chloroacetyl-3-methylphenoxyacetic acid.  3 - Chloro - 4 - (2 - methylene - butyryl)-phenoxyacetic acid and ethyl mercaptan gave 3 - chloro - 4 - [2 - (ethylmercaptomethyl) - butyryl] - phenoxyacetic acid; 4 - methacryloyl - 3 - chlorophenoxy acetic acid and thioglycollic acid gave 4-[2-(carboxymethylmercaptomethyl) - propionyl] - 3 - chlorophenoxyacetic acid and similarly 3-chloro-4-[2-(carbomethylmercaptomethyl) - butyryl] - phenoxyacetic acid.ALSO:Pharmaceutical compositions having diuretic, saluretic, natriuretic and chloruretic properties comprise compounds of the formula <FORM:0998835/A5-A6/1> wherein each of R, R1 and R2 is a hydrogen or halogen atom or a halomethyl, hydroxy, C1-5-aliphatic, C1-5-aliphatic-oxy, C1-5-aliphatic-thio, alicyclic, mononuclear aryl, mononuclear aryl substituted - C1-5 - aliphatic, mononuclear aryl substituted C1-5-aliphatic-thio, mononuclear acyloxy, or mononuclear arylthio radical with the proviso that not all of R, R1 and R2 are hydrogen atoms, or R and R2 are joined to form with the carbon atoms to which they are attached a 5- or 6-membered carbocyclic ring; each of R3, R4, R5 and R6 is a hydrogen atom or a halomethyl; C1-5 aliphatic, mononuclear aryl, C1-5 aliphatic-oxy, hydroxy, acylamino, or nitro radical or R3 and R4 are joined to form with the ring carbons to which they are attached a 5- or 6-membered carbocyclic ring; A is an oxygen or sulphur atom; B is a divalent C1-5-aliphatic, divalent C1-5 alkylene-oxy or divalent, C1-5-aliphatic-mononuclear aryl radical; and X is a hydroxyl or a salt of a hydroxyl radical or is an alkoxy, amino or hydrazino radical (in the above definitions the aliphatic residues may be straight- or branched-chain, saturated or unsaturated and may contain amino halomethyl, carboxyl, substituted carboxyl, hydroxyl, alkylthio, arylthio or nitro substituents; the alicyclic groups may also be substituted as for the aliphatic groups; the aryl, aryloxy, arythio and arylaliphatic groups may be substituted by C1-5 alkyl, C1-5 alkoxy, C1-5 alkylthio, hydroxy, or halomethyl groups or halogen atoms; and amides include substituted amides containing the group -NR7R8, where R7 and R8 are aliphatic or aromatic groups, either substituted or unsubstituted or R7 and R8 together with the adjacent N-atom form a heterocyclic ring) together with an inert, non-toxic pharmaceutical carrier. The compositions may also contain other diuretic or hypotensive agents or other therapeutic and/or nutritive agents and may be formulated as pills, capsules or tablets or in other forms suitable for oral administration.